That nicotine addiction sustains tobacco use for most smokers is well established. Once a person is addicted to nicotine, quitting smoking is difficult, and more than 90 percent of smokers who try to quit each year fail. It follows that an important component of a policy to reduce tobacco use in the population is to prevent development of nicotine addiction in young people. Young people do not start to smoke because they are addicted, but once they begin to smoke become addicted, which sustains smoking into adulthood. It is difficult to prevent adolescents from experimenting with cigarettes; however, by reducing the content of nicotine in tobacco products, it may be possible to prevent the transition from experimental smoking to addiction. The Food and Drug Administration has gained jurisdiction to regulate nicotine, but FDA does not know yet how best to do it. One of the most widely discussed proposals is a gradual reduction of the nicotine content of all cigarettes to a level that does not sustain nicotine addiction. Such a cigarette could prevent adolescents from becoming addicted, and might also serve to wean adult smokers to a lower level of addiction and, therefore, facilitate quitting. Of concern with such a policy is whether compensatory oversmoking of cigarettes will be harmful to already addicted smokers. This proposal aims to examine the safety of reducing the nicotine content of cigarettes gradually. Volunteer smokers will smoke research cigarettes with progressively reduced nicotine contents over three or six months, with concomitant assessment of exposure to tobacco smoke nicotine, gas and tar, using the biomarkers of blood and urinary cotinine, urinary nicotine and metabolites, carboxyhemoglobin, urinary mutagenicity, urine solanesol, as well as measurement of cigarette puffing behavior. To examine the importance of the rate of nicotine reduction, measurements will be made in smokers in conditions where nicotine content is tapered over 12 weeks compared to over 24 weeks. The proposed research is needed to guide the FDA as how best to regulate nicotine in cigarettes and is an essential first step in examining the feasibility of a national nicotine regulation program.